Sampling-based exploration of folded state of a protein under kinematic and geometric constraints

Peggy Yao, Liangjun Zhang, Jean-Claude Latombe

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Flexibility is critical for a folded protein to bind to other molecules (ligands) and achieve its functions. The conformational selection theory suggests that a folded protein deforms continuously and its ligand selects the most favorable conformations to bind to. Therefore, one of the best options to study protein-ligand binding is to sample conformations broadly distributed over the protein-folded state. This article presents a new sampler, called kino-geometric sampler (KGS). This sampler encodes dominant energy terms implicitly by simple kinematic and geometric constraints. Two key technical contributions of KGS are (1) a robotics-inspired Jacobian-based method to simultaneously deform a large number of interdependent kinematic cycles without any significant break-up of the closure constraints, and (2) a diffusive strategy to generate conformation distributions that diffuse quickly throughout the protein folded state. Experiments on four very different test proteins demonstrate that KGS can efficiently compute distributions containing conformations close to target (e.g., functional) conformations. These targets are not given to KGS, hence are not used to bias the sampling process. In particular, for a lysine-binding protein, KGS was able to sample conformations in both the intermediate and functional states without the ligand, while previous work using molecular dynamics simulation had required the ligand to be taken into account in the potential function. Overall, KGS demonstrates that kino-geometric constraints characterize the folded subset of a protein conformation space and that this subset is small enough to be approximated by a relatively small distribution of conformations. © 2011 Wiley Periodicals, Inc.
Original languageEnglish (US)
Pages (from-to)25-43
Number of pages19
JournalProteins: Structure, Function, and Bioinformatics
Volume80
Issue number1
DOIs
StatePublished - Oct 4 2011
Externally publishedYes

Fingerprint Dive into the research topics of 'Sampling-based exploration of folded state of a protein under kinematic and geometric constraints'. Together they form a unique fingerprint.

Cite this